NEW YORK – An international team led by investigators at QIMR Berghofer Medical Research Institute and the University of Queensland has identified hundreds of genetic loci that are linked to the volume of the brain or specific brain regions. Their results shed light on the genetics of variation within the human brain and the risk of related conditions such as Parkinson's disease.
"[O]ur findings advance the understanding of the brain's complex and polygenic genetic architecture, implicating multiple molecular pathways in human brain structure and [suggest] that multiple genetic variants of small effect size are likely to be involved in the development of specific brain volumes," corresponding author Miguel Rentería, a researcher at QIMR Berghofer and the University of Queensland, and his colleagues wrote in an article published in Nature Genetics on Monday.
Starting with genotyping data and brain volumes based on magnetic resonance imaging data for 74,898 participants of European ancestry from 19 countries, members of the "Enhancing Neuro Imaging Genetics through Meta-Analysis" or ENIGMA study conducted a genome-wide association study and meta-analysis focused on intracranial volume overall and volumes of nine subcortical regions: the brainstem, caudate nucleus, hippocampus, nucleus accumbens, amygdala, putamen, globus pallidus, ventral diencephalon, and thalamus.
"Subcortical brain structures are affected in most major neurological diseases, including psychiatric and developmental brain disorders," the authors explained. "These brain structures are involved in crucial daily functions, such as learning, memory, attention, motor control, and reward."
The team's search led to 254 independent loci linked to brain volume, including 161 new ones, which together accounted for up to 35 percent of the estimated variation in the subcortical brain phenotypes considered.
Through a series of follow-up analyses that brought in gene-level, single-cell RNA sequencing, expression quantitative trait locus, and other data, the investigators began untangling causal genes, cell type-specific expression patterns, and regulatory features underlying genetic variants that are associated with subcortical volume.
Together, the work "brings us closer to answering key questions about how genetics influences brain structure, and how we can potentially treat [related] conditions in the future," co-first author Luis García-Marin, a graduate student affiliated with QIMR Berghofer and the University of Queensland, said in a statement.
When the researchers focused on polygenic contributors to brain volume, meanwhile, they saw signs that polygenic scores established for subcortical brain volume measures or for intracranial volume could help understand brain volume variability within or across populations, since scores established with European data seemed to track with corresponding brain volumes in 1,833 individuals of African and 152 of Asian ancestry.
"[O]ur findings point toward polygenic score generalizability across individuals of diverse ancestral backgrounds and could be leveraged to study brain development in young populations," the researchers wrote, adding that "[w]ell-powered polygenic predictors will potentially … boost power of future neuroimaging GWAS performed in samples of underrepresented ancestries, an important endeavor to narrow the ancestry biases in current genetic studies."
Finally, the researchers' analyses helped establish relationships between genetic variants influencing the volume of different brain parts and genetic contributors to related neuropsychiatric conditions, particularly Parkinson's disease and attention-deficit hyperactivity disorder (ADHD).
While variants associated with increased volumes in eight parts of the brain coincided with an uptick in Parkinson's disease risk, for example, ADHD risk increased in the presence of genetic variants associated with diminished volume in three brain regions.
"There is strong evidence that ADHD and Parkinson's [have] a biological basis," Rentería said in a statement, "and this research is a necessary step to understanding and eventually treating these conditions more effectively."